Cigarette smoke is the major cause of COPD and lung cancer and studies have demonstrated that cigarette smoke can directly induce matrix metalloproteinase (MMP) expression in the lung parenchyma. Thus, it is essential that COPD research focuses on improving our understanding of the specific cellular and biochemical injury induced by smoke within the lung. It has been demonstrated that MMPs when expressed in the lung of transgenic mice, lead to the development of emphysema therefore documenting the critical role for MMPs in lung destruction. Also, our laboratory has identified increased expression of MMP1, a human collagenase, in the epithelial cell of patients with COPD and defined the molecular regulation of the smoke induced expression of MMP1. Also, we identified several novel polymorphisms within this cigarette smoke responsive element of the MMP1 promoter. It remains to be determined whether blockade of MMPs will protect the lung from destruction and disease initiated by cigarette smoke. Furthermore, the role of this newly defined cigarette smoke responsive element in MMP1 in disease susceptibility is not know. Therefore, we propose to perform the following studies. First, we will test the hypothesis we will determine through genetic and pharmacological methodology whether inhibition of the collagenolytic enzymes protects from the development of emphysema. We have within the laboratory the animal models and compounds available to complete this study. In the second aim we will identify whether blockade of the cigarette smoke induction pathway protects from lung inflammation and emphysema utilizing the mouse and rabbit model of smoke exposure. Preliminary studies have already identified candidate small molecules targeting this pathway. Finally, in collaboration with Dr. Edwin Silverman and Michael Cho we will translate our findings utilizing samples from the COPD gene Study. Here we will determine whether SNPs within MMP1, MMP13 or genes within the smoke induced pathway confer susceptibility to emphysema. Upon completion of this proposal our goal is to determine whether the collagenolytic enzymes are a therapeutic target in emphysema and whether this pathway is useful as a disease susceptibility marker. !